The present invention generally relates to absorbable, crystalline, monocentric, polyaxial copolymers having a crystalline component, and a flexible, amorphous component. More specifically, the invention relates to such copolymers wherein the flexible and/or the crystalline component of the polymer comprise lactide units. The invention also relates to a method of producing such copolymers, and products thereof. The copolymers of the invention exhibit improved compliance, and prolonged mechanical integrity in vivo.
Soft and pliable absorbable polymers are most often made as block or segmented copolymers consisting of an amorphous middle part and a terminal part having blocks or segments capable of crystallization. The amorphous middle part is made up of polyaxial chains, which result in a central component having a glass transition temperature below room temperature. The mobility of the polymer chains in the central component is thus high, and a relatively low mechanical force is required to displace segments of the polymer chains giving rise to the soft characteristics. The crystalline segments or blocks at the ends of each soft middle block or segment contribute to the overall material integrity and final mechanical strength. Such polymers made from linear initiators often possess a high percentage of crystalline phase and are often used in various suture materials where high mechanical strength are needed. However, in various soft and hard tissue applications where absorbable medical devices are sought for, the materials should preferably be as soft and pliable as possible to reduce the modulus mismatch between implant and tissue, which often can lead to unnecessary inflammatory response. One approach to further reduce the crystallinity and also the size of individual crystalline domains has been found to be to utilize tri- or tetra-functional initiators as previously disclosed in WO 0140348. Accordingly, WO 0140348 generally discloses absorbable, crystalline, monocentric, polyaxial copolymers having a crystalline component, and a flexible, amorphous component. The polymers can be prepared from a monomeric initiator, which is a tri- or tetra-functional organic compound, by reacting such initiator with at least one cyclic comonomer, selected from carbonates and lactones to form an amorphous polymeric, polyaxial initiator, and then reacting the amorphous, polymeric, polyaxial initiator with at least one lactone comprising a member selected from the group consisting of glycolide, lactide, p-dioxanone (1,4-dioxan-2-one), and combinations thereof. The copolymers are said to be crystallizable materials with melting temperatures above 100xc2x0 C., which can be melt-processed into highly compliant absorbable films and fibers. The polymers are primarily intended for use in medical absorbable devices, such as, for example, stents, sutures, sealing devices for closing a wound in a wall of a blood vessel. Examples of the latter can be found in EP-B-1169968.
The present inventors have now surprisingly found that by using lactide in the amorphous core component and/or the crystalline hard block or segment of the polymers generally described in WO 0140348 certain desirable properties of the said polymers can be obtained. More particularly, the use of lactide as comonomer in the amorphous central core has been found to produce copolymers having markedly increased toughness; and when lactide is used in the crystalline terminals, it has been found to yield materials with modulated high ultimate elongation through controlling the degree of crystallinity and extent of phase mixing between the amorphous core and crystalline terminals without compromising the ability to retain the device integrity and its mechanical properties over a longer period of time.
According to the present invention, it has been found that by using L-lactide, with or without a small fraction of one or more cyclic monomer such as trimethylene carbonate, D,L-lactide, 1,4-dioxan-2-one, 1,5-dioxepan-2-one and caprolactone, in the hard terminal crystalline segment of the absorbable copolymers prepared from tri- or tetra-functional initiators, absorbable, compliant copolymers having high ultimate elongation can be obtained. This is especially advantageous in devices, which may be deformed during the surgical procedure or be exposed to dynamic movements after implantation. Furthermore, these materials exhibit an increased period of stability after implantation compared to similar materials where the hard crystalline segment is derived exclusively, or mostly, from glycolide. This is especially important in such applications where the material should act as a barrier to separate tissues where at least one of the tissues regenerates at slow speed compared to other adjacent tissues. An increased period of stability is also important from a biocompatibility point of view. When degradation starts shortly after implantation of the absorbable device, the degradation products, although non-toxic, may contribute to a more intense inflammation and also more scar tissue formation, which normally is an unwanted type of tissue regeneration. These copolymers will retain their mechanical properties over longer periods of time as compared to the similar polymers also when glycolide is used in the soft amorphous core.
The present inventors have also surprisingly found that by using a small amount of lactide in the amorphous segments, the copolymers will have a markedly reduced sensitivity to moisture, and thus improved storage life. It has also been found that such copolymers will exhibit prolonged mechanical retention in vitro and when stored in a humid environment. Thus, incorporation of D,L-lactide-based sequences in the amorphous core of about 2 percent, by mole, based on the overall composition of the copolymer is sufficient to produce the effects of the invention.
The copolymers of the invention especially find applicability in medical absorbable implants, wherein the material should possess high flexibility and also a low Young""s modulus combined with a longer functional lifetime of the device in vivo.
Accordingly, in one aspect the present invention is directed to an absorbable, crystalline, monocentric, polyaxial copolymer exhibiting improved mechanical properties, having at least three axes originating and extending outwardly from the centre of the copolymer, which centre is formed from an at least tri- or tetra-functional initiator molecule, each axis including an amorphous, flexible component adjacent to and originating from the centre, the amorphous component being formed of repeat units derived from at least one cyclic monomer selected from the group consisting of carbonate and lactones, and a rigid, crystallizable component extending outwardly from the amorphous, flexible component, the crystallizable component being formed of repeat units derived from at least one lactone, wherein lactide is contained in at least one of said components of said copolymer.
In one embodiment, a copolymer exhibiting improved storage life and reduced sensitivity to moisture is provided, containing lactide in the amorphous component.
In another embodiment, a copolymer exhibiting high flexibility and elongation to break as well as prolonged period of stability after implantation and reduced sensitivity to moisture is provided, containing lactide in the crystalline component.
In a further embodiment, both components comprise lactide units, thus combining the characteristics of the two-lactide containing components.
According to another aspect the present invention relates to polymeric, polyaxial lactide-containing initiators (PPIs), from which PPIs the copolymers can be prepared.
In a further aspect the present invention relates to a method of preparing the present copolymers.
According to still another aspect of the present invention the subject copolymer is converted to different forms of absorbable stents, a tubular mantle (or cover) for stents, sutures, sealing devices or parts of multicomponent sealing devices for closing (or plugging) a wound or a needle hole in a wall of a blood vessel, such as described in e.g. EP-B-1169968.
In one embodiment, a composite cover or mantle (such as shown in FIGS. 3-5) for a stent which includes a polymeric matrix reinforced with monofilament cross-spirals may be provided, wherein the matrix, the monofilaments or both may be made of the copolymer of the present invention.
In another embodiment the present invention is directed to a device for sealing a puncture in a blood vessel, such as shown in FIG. 1. The sealing device comprises basically a first sealing member to be positioned against the inner wall of a blood vessel, a second sealing member to be positioned against the outer wall of the blood vessel, and an elongated member that extends through the vessel wall and connects the first member to the second member.
Preferably, the first sealing member, the second sealing member, or both are formed from an absorbable polymer. Most preferably, at least one of the first sealing member and the second sealing member comprise an absorbable, crystalline, monocentric, polyaxial copolymer which includes a central atom selected from the group consisting of carbon and nitrogen; and at least three axes originating and extending outwardly from the central atom, each axis including: an amorphous, flexible component adjacent to and originating from the central atom, the amorphous component consisting of repeat units derived from at least one cyclic monomer selected from the group consisting essentially of carbonates and lactones; and a rigid, crystallizable component extending outwardly from the amorphous, flexible component, the crystallizable component consisting of repeat units derived from at least one lactone.
Preferably, the elongated member comprises a composite of a highly flexible sheath and a less flexible solid, monofilament core, the less flexible core within the sheath comprising the enlarged cross-sectional diameter of the distal locking portion of the elongated member composite. It is preferred that the sheath is a braided suture with a strength retention profile that exceeds those of other components of the device, and the less flexible filament is threaded through the interior portion of the suture. It is also preferred that the ends of the filament are tapered. In one embodiment the less flexible filament is sufficiently flexible to compress and frictionally engage the opening defined within the second sealing member.
Further embodiments and advantages will be evident to skilled reader from the following detailed description.